In examinations of internal organ wherein the difference in X-ray absorption between the organ and adjacent tissues thereof is small, ‘contrast agents’ having different absorption rates are used to increase the difference in X-ray absorption. There are two types of the contrast agents, i.e., positive contrast agents that absorb X-ray well and negative contrast agents that transmit X-ray well, and a proper type is used according to the examination purpose.
Iopromide of the following formula (1) has been widely used as a contrast agent for X-ray. The processes for preparing iopromide are disclosed in U.S. Pat. No. 4,364,921 (Schering Corporation, Germany) and Korean Patent No. 10-0286639.

U.S. Pat. No. 4,364,921 discloses three preparation processes of iopromide. One of them is shown in the following reaction scheme 1.

According to the above reaction scheme 1, iopromide of formula (1) is prepared through the steps of reacting 5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) with methoxyacetyl chloride in dimethylformamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3), and reacting the compound of formula (3) with 2,3-dihydroxypropylamine and in turn with 2,3-dihydroxy-N-methylpropylamine in dimethylformamide solvent in the presence of basic material.
However, in the preparation step of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride of formula (4) by the reaction of the compound of formula (3) with 2,3-dihydroxypropylamine according to the above reaction scheme 1, a second 2,3-dihydroxypropylamine is further added to the compound of formula (4) to form a bismer by-product, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid-N,N′-bis(2,3-dihydroxypropyl)diamide of formula (5) in a large amount through the pathway of the following reaction scheme 2.

Accordingly, the inevitably produced bismer by-product of formula (5) should be removed in order to obtain iopromide with high purity. In the process according to the reaction scheme 1, the bismer by-product can be removed through a number of steps of crystallization and filtration with using large amounts of several organic solvents. However, the process according to the reaction scheme 1 must employ a number of purification steps, becomes more complicated and finally, has a demerit of decrease in productivity and in yield.
The other two processes disclosed in U.S. Pat. No. 4,364,921 are those basically under the same concept as shown in the following reaction schemes 3 and 4.


In the above reaction schemes 3 and 4, along with modifying the functional groups to be reacted, 5-nitroisophthalic acid monomethylester of formula (7) as a starting material is reacted with 2,3-dihydroxy-N-methylpropylamine and in turn with 2,3-dihydroxypropylamine. In these processes, there is an advantage of preventing the generation of the compound of following formula (6), a bismer by-product which may be formed by a further addition of 2,3-dihydroxy-N-methylpropylamine through a pathway similar with reaction schemes 1 and 2.

However, these processes require many steps to modify the functional groups to be reacted and also require a number of filtration and drying steps to purify the intermediates in almost every step. Therefore, similarly to the preparation process of reaction scheme 1, they are not able to avoid the low productivity and the low yield, and have a severe demerit of difficulty in industrial application.
Because of those problems being involved in the conventional processes as mentioned above, there is a considerable need to an economical process for preparing the highly pure iopromide in high yield by the effective removal of a bismer by-product.